(S)-(−)-1-(4-Fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4-homopiperazine hydrochloride is a compound which is represented by the following formula (1);

and which is known to be a useful prophylactic and therapeutic agent for cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoidal hemorrhage, and cerebral edema, particularly a suppressor for cerebrovascular spasm such as cerebral stroke (see Patent Document 1).
In the synthesis of compound (1), 4-fluoroisoquinoline-5-sulfonyl chloride represented by formula (2a):
or a salt thereof is known to be an important intermediate (Patent Document 1).
For reactions to form an aromatic sulfonyl chloride, approaches such as acid-halogenation of sulfonic acid in which an aromatic ring is sulfonated with fuming sulfuric acid, and the sulfonated ring is reacted with phosphorus pentachloride or phosphorus oxychloride (see Non-Patent Document 1); chlorosulfonylation employing chlorosulfuric acid (see Non-Patent Document 2); reaction between sulfinic acid and chlorine or a chloride (see Non-Patent Document 3); synthesis from a diazonium salt; chlorination of a thiol or disulfide (i.e., sulfone derivative in a low oxidation state) in an aqueous solution; trapping a Grignard reagent or an organic lithium reagent with sulfuryl chloride; and Friedel-Craft reaction employing sulfuryl chloride and a Lewis acid have been known.
Among these approaches, some are employed also for producing a variety of isoquinolinesulfonyl chlorides. For example, chlorosulfonylation employing chlorosulfuric acid (see Non-Patent Document 4), acid-halogenation of sulfonic acid (see Non-Patent Document 5), and synthesis from a diazonium salt (see Patent Document 2) are employed in practice.
However, only a limited number of approaches have been reported for production of 4-fluoroisoquinoline-5-sulfonyl halide, and all the reported approaches are based on synthesis from a diazonium salt (see Patent Documents 1 and 3 to 5). Among these documents, Patent Document 1 discloses the sole known approach employing the following scheme.

Specifically, 4-fluoroisoquinoline (3) is nitrified with potassium nitrate in sulfuric acid, to thereby form 4-fluoro-5-nitroisoquinoline (4a) and a position isomer (4b) thereof [step A]. Subsequently, these two products are reduced by use of concentrated hydrochloric acid and stannous chloride dihydrate, to thereby form 4-fluoro-5-aminoisoquinoline (5a) and a position isomer (5b) thereof [step B]. 5-Amino-4-fluoroisoquinoline (5a) is separated through column chromatography for purification [step C]. The purified product is diazotized with sodium nitrite [step D]. The diazo compound is subjected to Sandmeyer reaction employing SO2 gas-saturated acetic acid and cupric chloride dihydrate [step E], to thereby yield 4-fluoroisoquinoline-5-sulfonyl chloride (2a).
In the aforementioned reaction scheme, the synthesis of compound (2a) from compound (3) requires five steps in total, the steps including chromatographic purification and a step of producing an unstable diazonium salt. Therefore, there has been demand for a production process which realizes more direct and effective introduction of a sulfonyl halide group into the 5-position of isoquinoline through simple operation.
[Patent Document 1] International Laid-Open WO99/20620
[Patent Document 2] EP No. 350403
[Patent Document 3] EP No. 1122254
[Patent Document 4] International Laid-Open WO99/54306
[Patent Document 5] International Laid-Open WO97/28130
[Non-Patent Document 1] Org. Synth., I, 84(1941)
[Non-Patent Document 2] J. Amer. Chem. Soc., 70, 375(1948)
[Non-Patent Document 3] Ann., 565, 203(1949)
[Non-Patent Document 4] Synthetic Communications, 33(19), 3427(2003)
[Non-Patent Document 5] J. Med. Chem., 34(1), 73(1991)